Several recent reports have found significant associations between periodontal disease, tooth loss and increased coronary heart disease (CHD). Possible associations between dental caries and CHD and between dental disease and stroke have also been reported. Recent literature also supports the possible role of other chronic bacterial and viral infection, fibrinogen and other inflammatory mediators in increasing CHD risk. We propose to study the relation between periodontal disease, caries and tooth loss, and risk of incidence of coronary heart disease and stroke and to assess if these associations are independent of common risk factors including behavioral factors. Additionally, we propose to evaluate two possible explanations for these associations: (1) tooth loss leads to reduced masticatory efficiency, which could lead to reduced intake of dietary antioxidant and fiber, which in turn has been associated with increased risk for cardiovascular disease; and (2) chronic dental disease could lead to hyperfibrinogenemia which is strongly and probably causally associated with increased risk of CHD. We will also evaluate C-reactive protein, von Willebrand factor, tissue plasminogen activator, and Factor VII as additional mediators. Participants include 51,529 men enrolled in the Health Professionals Follow-Up Study since 1986 and 90,000 females enrolled in the Nurses Health Study since 1976 who reported their dental status in 1992. The follow-up in these cohorts is excellent and has been consistently over 90 percent. The outcome measures will include incident cases of CHD and stroke in 15 years of follow-up among men and 9 years of follow-up among women free of cardiovascular disease and cancer at baseline. Over 4500 incident cases of CHD and stroke are anticipated. Biomarker assays will be performed for a sub-population consisting of new CHD cases incident after the time of initial blood collection, and one matched control per case. Blood samples were provided by 32,000 nurses in 1989-90 and by 18,100 male health professionals in 1993-94, allowing for sufficient follow-up to include an estimated 600 incident cases among males and 600 cases among females for the biomarker analyses. The high prevalence of dental infection makes its potential association with inflammatory and dietary mediators, and ultimately increased risk of CHD and stroke very important with implications for millions of Americans.